# US 11,999,731 B2 · EGFR dimer disruptors and use of the same

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- Number: US 11,999,731 B2
- Document ID: US11999731B2
- Status: Granted
- Kind: B2
- Application number: 17/739,358
- Filed: 2022-05-09
- Published: 2022-10-27
- Granted: 2024-06-04
- Earliest claimed: 2018-02-23
- Assignees: The Regents of the University of Michigan
- Applicants: The Regents of the University of Michigan
- Inventors: Mukesh K. Nyati; Theodore S. Lawrence; Christopher Whitehead; Jason Christopher Rech; Brennan Taylor Watch
- Web page: https://patentgrep.com/patent/US11999731B2

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 471/10: Spiro-condensed systems
- C07D 233/70: One oxygen atom
- C07D 233/84: Sulfur atoms
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein are compounds that modulate EGFR and methods of using the same, for example to treat cancer.

## Claims

### Claim 1

A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula I:
wherein
X is S—C0-6alkylene, and said alkylene is optionally substituted with 1-3 groups independently selected from halo, N(R3)2, and OR3;
Y is null;
A is C6-10 aryl optionally substituted with 1 to 3 R4;
B is 5-10 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S, and said heteroaryl is optionally substituted with 1 to 3 R5;
R1 and R2 together with the carbon atom to which they are attached form a 6 membered heterocycloalkyl ring, wherein the heterocycloalkyl ring has 1 or 2 ring heteroatoms selected from O, S, and N, and wherein said cycloalkyl ring or heterocycloalkyl ring is optionally substituted with 1-2 R6;
each R3 is independently H or C1-6 alkyl;
each R4 and R5 is independently C1-6 alkyl, C1-6 haloalkyl, halo, or C1-6 alkoxy; and
R6 is C1-6 alkyl, C1-6 haloalkyl, (C═O)R3, (C═O)OR3, CON(R3)2, C0-3alkylene-C3-8cycloalkyl, C0-3alkylene-C6-10aryl, or C0-3alkylene-(5-10 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S), wherein the aryl or heteroaryl is optionally substituted with 1 to 3 R5.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein R1 and R2 together with the carbon atom to which they are attached form a heterocycloalkyl ring having the structure:
where * indicates the point of attachment to the rest of the compound of Formula I.

### Claim 3 (depends on 1)

The compound or salt of claim 1, wherein R6 is C1-6 alkyl.

### Claim 4 (depends on 3)

The compound or salt of claim 3, wherein R6 is methyl.

### Claim 5 (depends on 1)

The compound or salt of claim 1, wherein A is phenyl.

### Claim 6 (depends on 1)

The compound or salt of claim 1, wherein B is quinolinyl.

### Claim 7 (depends on 1)

The compound or salt of claim 1, wherein A is substituted with one R4.

### Claim 8 (depends on 7)

The compound or salt of claim 7, wherein A has the structure:

### Claim 9 (depends on 1)

The compound or salt of claim 1, wherein at least one R4 is halo.

### Claim 10 (depends on 9)

The compound or salt of claim 9, wherein R4 is bromo.

### Claim 11 (depends on 1)

The compound or salt of claim 1, wherein R3 is H.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising the compound or salt of claim 1 and a pharmaceutically acceptable carrier or excipient.

### Claim 13 (depends on 1)

A method of treating cancer associated with aberrant EGFR activity, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt of claim 1.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R1 and R2 together with the carbon atom to which they are attached form an unsubstituted 6 membered heterocycloalkyl ring.

### Claim 15 (depends on 14)

The compound of claim 14, wherein the heterocycloalkyl ring has 1 ring N atom.

### Claim 16

A compound which is compound 8C:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

A pharmaceutical composition comprising the compound or salt of claim 16 and a pharmaceutically acceptable carrier or excipient.

### Claim 18 (depends on 16)

A method of treating a cancer associated with aberrant EGFR activity, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt of claim 16.

### Claim 19 (depends on 18)

The method of claim 18, wherein the cancer is non-small cell lung cancer.

### Claim 20 (depends on 13)

The method of claim 13, wherein the cancer is non-small cell lung cancer.